First-in-human study of ABBV-011, a seizure-related homolog protein 6 (SEZ6)–targeting antibody-drug conjugate, in patients with small cell lung cancer.
Authors: Daniel Morgensztern, Neal E. Ready, Melissa Lynne Johnson, Afshin Dowlati, Noura J. Choudhury, David Paul Carbone, Eric S. Schaefer, Susanne M. Arnold, Sonam Puri, Zofia Piotrowska, Aparna Madhukeshwar Hegde, Anne C. Chiang, Wade Thomas Iams, Anthony W. Tolcher, Kaname Nosaki, Jiuhong Zha, Rui Li, Pooja Hingorani, Edwin E. Jeng, Muhammad Furqan
Journal: Journal of Clinical Oncology (2023)

3002 Background: Small cell lung cancer (SCLC) has a dismal prognosis and new therapies are urgently needed. SEZ6 is a transmembrane protein expressed in SCLC tumors that may be used as a therapeutic target. ABBV-011 is an antibody-drug conjugate (ADC) targeting SEZ6 with a calicheamicin payload, which has shown antitumor activity in preclinical models of SCLC. Preliminary results from the monotherapy dose-escalation and -expansion cohorts of the first-in-human ABBV-011 study are presented. Methods: Phase 1, open-label, multicenter study (NCT03639194) of ABBV-011 alone or in combination with budigalimab, a programmed cell death 1 inhibitor. Primary objectives were to assess the safety and tolerability and to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose of ABBV-011. Adults (≥18 years) with relapsed/refractory SCLC (1–3 lines of prior therapy) were enrolled. Dose escalation was guided by Bayesian continual reassessment method. ABBV-011 was administered intravenously at doses from 0.3 to 2.0 mg/kg once every 3 weeks. Dose expansion was conducted in SEZ6-selected patients. Results: At data cutoff on August 22, 2022, 99 patients were treated with ABBV-011 monotherapy. Median age was 63 years (range, 41–79), 50% of patients were male, and 68% had received ≥2 prior therapies. ABBV-011 ADC pharmacokinetics were approximately dose-proportional with an elimination half-life of 4.6 days across the dose range of 0.3–2.0 mg/kg. In dose escalation (n=26), 1 patient had a dose-limiting toxicity of grade (G) 3 fatigue at 2.0 mg/kg. We report safety and efficacy results for 40 patients in the dose-expansion 1.0-mg/kg ABBV-011 cohort. Median duration of treatment was 12 weeks (range, 1.9–63.3). Treatment-emergent adverse events (TEAEs) occurred in 39 (98%) patients, the most frequent being fatigue (48%), nausea (45%), anorexia (38%), thrombocytopenia (38%), and vomiting (35%). G3 TEAEs occurred in 18 (45%) patients, the most frequent being fatigue, thrombocytopenia, and neutropenia (10% each); 1 G4 TEAE of dyspnea was reported. Seven patients died due to malignant neoplasm/disease progression (n=6) or respiratory distress (n=1); none were related to ABBV-011. Hepatotoxicity was observed, including G≥2 TEAEs of hyperbilirubinemia (18%), increased gamma-glutamyltransferase (8%), ascites (5%), veno-occlusive liver disease (3%), and portal hypertension (3%). Confirmed objective response rate was 25% (10 partial responses [PR]), with median duration of response of 4.2 months (95% CI: 2.6, 6.7). Clinical benefit rate (CBR) was 65% (10 PR and 16 stable disease) and CBR lasting &gt;12 weeks was 43%. The median progression-free survival was 3.5 months. Conclusions: The MTD was not reached and ABBV-011 was well tolerated at 1.0 mg/kg with promising antitumor activity observed. Further evaluation of ABBV-011 is ongoing. Clinical trial information: NCT03639194 .